Electrolytic reduction of aromatic steroids



United States Patent 3,444,057 ELECTROLYTIC REDUCTION OF AROMATIC STEROIDS Lewis J. Throop, Los Altos, Calif., assignor to Syntex Corporation, Panama, Panama, a corporation of Panama No Drawing. Filed June 29, 1966, Ser. No. 561,362 Int. Cl. B01k 1/00 US. Cl. 204-59 10 Claims This invention relates to a novel process for the production of 19-nor-steroids. More particularly, this invention relates to a novel process for the production of 19- nor-steroids which involves electrolytically reducing an aromatic steroid to the corresponding 2,5 (10)-diene derivative followed by acid hydrolysis.

Heretofore, the preparation of 19-nor-steroids has been accomplished by the Birch method which involves treating an aromatic steroid with an alkali metal, e.g., sodium, in liquid ammonia with or without a cosolvent, and a proton donor such as ethanol to obtain the 2,5 (10)-derivative which upon treatment with acid results in the formation of a A -19-noror a A -19-nor-steroid depending upon the severity of the acid treatment. This and other prior art methods suffer from several drawbacks notable among which are the disadvantages of insolubility or very low solubility of the aromatic steroid in liquid ammonia, relatively low yields of the 2,5 )-diene intermediate and the difliculties encountered in recovering the product in pure form.

A primary object of the present invention is to provide a process for the production of 19-nor-steroids which overcomes the aforementioned disadvantages. Another object of the present invention is to provide a process for the reduction of an aromatic steroid which furnishes a high yield of the corresponding 2,5(10) diene steroid. Additional objects will become apparent as the invention is hereinafter described in detail and from the appended claims.

In accordance with the present invention, 19-nor-3-oxo steroids are prepared by converting an aromatic steroid into the corresponding 2,5(10)-diene steroid by subjecting said aromatic steroid to electrochemical reduction at a cathode such as aluminum, carbon, copper, graphite, lead and platinum in an electrolytic medium comprising a lithium salt electrolyte and a solvent such as a lower aliphatic amine, liquid ammonia, and mixtures thereof and thereafter treating said 2,5(10)-diene steroid with an acid to obtain said 19-nor-3-oxo steroid. The electrolytic medium may optionally contain a cosolvent such as an ether, e.g., diethyl ether, tetrahydrofuran, dioxane, a lower monohydric alcohol such as isopropanol, methanol, ethanol, and the like.

Preparation of 19-nor-steroids according to the present invention can be illustrated as follows. For the sake of simplicity, a partial formula showing rings A and B of the steroid nucleus is shown.

I I R0 R0 l I I o: o I

(IV) (III) In the above formulas, R represents a lower alkyl group such as methyl, ethyl, propyl, t-butyl, hexyl, n-pentyl, and the like, a lower cycloalkyl group such as cyclopropyl, cyclopentyl, cyclobutyl, and the like, or an aralkyl group such as benzyl and the like.

As illustrated by the partial formula I above, the process of the present invention is applicable to steroids having an aromatic ring. Steroids utilized as starting materials include the A -trienes of the estrane, 19-nor-pregnane, and 19-nor-cholestane series such as the 3-alkyl ether, 3-cyc1oalkyl ether or 3-aralkyl ether of 3-hydroxyestra-1,3,5(10)-trien-17-one, estra-1,3,5 10) triene-3,175- diol, 18-methylestra-1,3,5 (10)-triene-3,17/3-diol, l7oc-Sllbstituted derivatives such as 17a-methy1estra-1,3,5(10)- triene-3,17/8-diol, 17a vinylestra-1,3,5-(10)-triene-3,17B- diol, 17a-ethinylestra-1,3,5(10)-triene-3,17fi-diol, 17-cycloalkylenedioxyestra 1,3,5(10)-trien-3-ol such as 17-cycloethylenedioxy, 17-cyclopropylenedioxy, and the like, 1713-fluoroethoxyestra-1,3,5(10)-trien-3-ol, 17B hydroxyethoxyestra-1,3,5(10)-trien-3-ol, 173 alkoxyestra 1,3,5 (10)-trien-3-ol such as 17,8-rnethoxy, 17fl-ethoxy, and the like, estra-1,3,5(10) triene 3,115,17fl-triol, estra-1,3,5 (10)-triene-3,l6a,17fl-triol, 3-hydroxy-l8-nor -D homoestra-1,3,5(10)-trien-17-one, D-homoestra-1,3,5(10),8(9)- tetraene-3,17fl-diol, 17 cycloethylenedioxy-D-homoestra- 1,3,5 (10),8(9)-tetraen-3-ol, 17 cycloethylenedioxy- D- homoestra-1,3,5(10),8(9),14-penten-3-ol, and the like, 19- nor-cholesta-l,3,5(10)-trien-3-ol, 19 nor pregna 1,3,5 (10)-trien-3-ol, 3-hydroxy-19-nor-pregna-1,3,5(10)-trien- 20-one, ZO-ketals such as 20-cycloethylenedioxy-19-norpregna-1,3,5(1=0)-trien 3 ol, 20-cycloethylenedioxy-19- nor-pregna-1,3,5(10)-triene-3,11p-diol, 1 methy1-19-nor- 20-cycloethylenedioxypregna-1,3,5 (10) -trien-3-ol, 20-cycloethylenedioxy 19 nor-pregna-1,3,5(10)-triene-3,11B, 17a,21-tetrol, 17a,20;20,2l-bismethylenedioxy 19 norpregna-1,3,S(10)-trien-3-ol, and the like, preferably the 3-methyl ether of the foregoing steroids. In the case of aromatic steroids containing an unprotected 0x0 or keto group, said group is reduced to the free alcohol during the reduction of the aromatic steroid I to the 2,5 10)- diene steroid II. Thus, before reducing the aromatic ste roid, if desired, the 0x0 group can be protected by e.g., formation of the ketal which can be removed during the conversion of the 2,5 10)-diene derivative (II) to the 19-nor-steroid (III or IV). Alternatively, upon completion of the reaction, the free alcohol containing steroid can be oxidized, if desired, to the corresponding oxo compound as by treatment with chromium trioxide in acetic acid or pyridine, or the like.

Electrolytes employed in the reduction of an aromatic steroid according to the process of the present invention include lithium chloride, lithium bromide, lithium iodide and mixtures thereof. The amount of electrolyte can vary from about 1% to about 20% by weight of the electrolytic medium, preferably from about 2% to about 15%.

Solvents which are employed in the electrochemical reduction include low molecular weight aliphatic amines, liquid ammonia, and mixtures thereof in which the electrolyte is soluble. Generally, the aromatic steroid starting material is sutficiently soluble in the foregoing solvents or mixtures thereof; however, particularly in the case of liquid ammonia, an anhydrous co-solvent can be employed to assist in forming a solution. Suitable cosolvents include the ethers such as tetrahydrofuran, diethyl ether, dioxane, and the like, lower monohydric alcohols such as isopropanol, ethanol, methanol, and the like, polyhydric alcohols such as ethylene glycol, propylene glycol, and the like. Lower aliphatic amines employed in the process of the present invention include, for example, ethylenediamine, ethylarnine, methylamine, n-butylamine, 1,3-propanediamine, and the like. In employing a mixture of one or more aliphatic amines with liquid ammonia as the solvent medium, the proportion of amine and liquid ammonia can vary considerably. Generally, in using a mixture of solvents, it is more advantageous to employ a major amount of the aliphatic amine because of the low solubility of some aromatic steroids in liquid ammonia and the necessity of working at very low temperatures to avoid evaporation of the liquid ammonia.

Reduction of an aromatic steroid into a 2,5(10)-diene steroid in accordance with the present invention utilizes an undivided electrolysis cell preferably containing a cathode of high surface area made of conductive material such as aluminum, carbon, lead, copper, or graphite. Although aluminum, carbon, lead, copper and graphite are preferred, other conductive materials may also be used such as platinum. More preferably, the cathode is an aluminum cathode of high surface area such as aluminum, aluminum alloys, aluminum plated materials, and the like. Anode materials which are used in the electrolytic reduction include any difficultly oxidizable conductor such as carbon, graphite, iron, lead, platinum, and the like.

In electrolytically reducing an aromatic steroid according to the process of the present invention, a current density within the range of about 0.001 to about 0.2 ampere per square centimeter, preferably about 0.003 to 0.1 amp/cm. is employed. Depending primarily upon the current density and the current efliciency, a reaction time of the order of about 1 to about 16 hours is sufficient to accomplish reduction of the aromatic steroid. The most beneficial reaction time for the reduction of a particular aromatic steroid is readily determinable by one of ordinary skill in the art giving due consideration to such factors as the current density, current efliciency, concentration of steroid, cathode material, temperature, and the like. As a rule, a current within the above limits is applied for a time sutficient to pass the equivalent of at least two Faradays per mole of steroid of electric current at the current employed. However, in view of the fact that an electrolysis system normally operates at a current efiiciency of from about forty to eighty percent, a greater amount of electricity is usually employed. Thus, for a system operating at about fifty percent efliciency, the equivalent of at least four Faradays, preferably in slight excess thereof, per mole of steroid is employed.

The reaction temperature depends upon such factors as the solvent employed, the electrodes, and the like. If liquid ammonia is used as the solvent, the reaction temperature will necessarily be very low, i.e., about 30 C. to about 50 C. to avoid loss of the solvent by evaporation before the electrochemical reduction is complete. Higher temperatures can be employed giving consideration to the boiling point of the particular solvent used. Generally, the efiiciency of the electrochemical reduction decreases as the reaction temperature increases substantially above about 60 C.

The concentration of aromatic steroid starting material can vary considerably. Concentrations within the range of about 0.1% to about 20% by weight of the electrolytic medium are suitable, preferably about 1% to 15%. A higher concentration of aromatic steroid can be used in which case the 2,5'(10)-diene produced should be soluble or at least partially soluble in the solvent medium.

Upon completion of the electrochemical reduction of the aromatic steroid into the corresponding 2,5(l)-diene intermediate, the intermediate is treated with acid in an aqueous organic solvent according to procedures well known to those skilled in the art to obtain either a M -3- one steroid (-III) or a 1-nor-A -3-one steroid (IV). Thus, by treating the 2,5()-diene intermediate with a mineral acid such as hydrochloric acid, sulfuric acid, and the like in aqueous alcohol, e.g., methanol, ethanol, and the like, for a period of time of the order of about fifteen minutes to about 16 hours or more at room temperature or above, a 19-nor-A -3-one steroid is obtained. Treatment of the 2,5(10)-diene intermediate with an organic acid, e.g.,

4 oxalic acid, acetic acid, and the like, in aqueous alcohol furnishes the A500) steroids (111).

The following examples serve to illustrate but are not intended to limit the present invention. Unless otherwise stated, all parts are expressed as parts by weight and the reaction temperature is room temperature.

EXAMPLE 1 Into a single compartment glass electrolytic cell having a volume of about 50 cc. provided with an aluminum cathode and aluminum anode, each electrode measuring 1 cm. x 4 cm. x 1.6 mm., there is added 30 ml. of anhydrous ethylenediamine, 200 mg. of 3-methoxy-l7-cycloethylenedioxyestra1,3,5(l0)-triene, and 2 g. of lithium chloride. The mixture is stirred briefly and a cover fitted with a calcium chloride condenser placed on the cell. A current of 0.04 ampere is then applied for three hours. Thereafter, the reaction mixture is poured into 150 ml. of cold Water, allowed to stand for about one hour, and filtered to furnish 3-methoxy-17-cycloethylenedioxyestra- 2,5 l0)-diene.

EXAMPLE 2 Into a single compartment electrolysis cell provided with two aluminum electrodes, each measuring 1 cm. x 4 cm. x 1.6 mm., there is added 1 g. of lithium chloride, with stirring, and 30 ml. of anhydrous ethylenediamine containing mg. of 3-methoxy-17-cycl0ethylenedioxyestra-l,3,5(l0)-triene and 0.5 ml. of anhydrous isopropyl alcohol. A current of 20 milliamperes is then applied for about 4 hours while maintaining the temperature at about 30 C. Thereafter, the reaction mixture is poured into about ml. of water and filtered after standing for about 1 hour to furnish 3-methoxy-l7-cycloethylenedioxyestra-2,5(10)-diene. A mixture of the above 2,5 l0) -diene steroid, 20 ml. of ethanol, and 2 ml. of 37% hydrochloric acid is then allowed to stand at room temperature for 15 hours. Thereafter, the mixture is poured into water and extracted with methylene chloride. The methylene chlo ride extracts are washed with water, dried and evaporated to dryness to yield estr-4-ene-3,17-dione.

EXAMPLE 3 Into an electrolysis cell provided with an aluminum cathode and aluminum anode, each of about 4 cm. there is added 30 ml. of anhydrous ethylenediamine, 0.5 ml. of anhydrous methanol, 100 mg. of 3-methoxy-l7-cycloethylenedioxyestra-1,3,5(10)-triene, and 1 g. of lithium chloride. A current of about 20-25 milliamperes is then applied for 4 hours while maintaining the temperature at about 3035 C. The reaction mixture is then diluted with water and extracted with chloroform. The chloroform extracts are then washed with water, dried and evaporated to yield 3-methoxy-l7-cycloethylenedioxyestra-2,5 (10)-diene.

A mixture of the above 2,5(10)-diene steroid, 15 ml. of 90% aqueous methanol and 1 g. of oxalic acid is stirred briefly and then allowed to stand at room temperature for about two hours. The reaction mixture is then poured into water and extracted with methylene chloride. The methylene chloride extracts are washed with water, dried and evaporated to dryness to yield estr-5(10)-ene-3,17- dione.

EXAMPLE 4 The process of Example 1 is repeated with the exceptions that the current is applied for about 5.5 hours and the reaction temperature is maintained at about 30 C. Using the compounds listed under Column I as the starting material, the corresponding 2,S(10)-diene compounds listed under Column 11 are obtained.

I II

3methoxyestra-1,3,5(10)-trien-17- 3-methoxyestra-2,5(10)-dien-17fl ol.

one.

3-methoxyestra-1,3,5(10)-trien-l7B-ol. 3-methoxyestra-2,5(10)-dien-17fi-01.

1704,20;20,21-bismethylene-dioxy-19- 1704,20;20,21-bismethylene-dioxy-19- nor-pregna-l,3,5(l0)-trieu-3-0l-3- nor-pregna-2,5,()-dien-3-ol-3- 3-methoxy-20cycloethylene-dioxy- 19-nor-pregna 1,3,5(10)triene.

nor-pregna-Z,5(10)-diene.

What is claimed is:

1. A process for the production of l9-nor-3-oxo steroids which comprises reducing an aromatic steroid by electrochemical reduction at a cathode selected from the group consisting of aluminum, carbon, copper, lead, graphite and platinum in an electrolytic medium comprising a solvent selected from the group consisting of a lower aliphatic amine, liquid ammonia, and mixtures thereof and an electrolyte selected from the group consisting of lithium chloride, lithium bromide and lithium iodide to obtain the corresponding 2,5(l0)-diene steroid, and subjecting said 2,5(lO)-diene to acid hydrolysis to obtain said l9-nor-3- 0x0 steroid.

2. A process according to claim 1 wherein said aromatic steroid is selected from the group consisting of 3-alkyl ethers, 3-cycloalkyl ethers, and 3-aralkyl ethers of 1,3,5 (10)-trienes of the estrane, l9-nor-pregnane, and 19-norcholestane series.

3. A process according to claim 2 wherein said cathode is aluminum, said solvent is ethylenediamine, and said electrolyte is lithium chloride.

4. A process according to claim 3 wherein said aromatic steroid is 3-methoxy-17-cycloethylenedioxyestra-1,3,5 10) -triene.

5. A process according to claim 4 wherein said acid hydrolysis is accomplished by treating said 2,5(10 )-diene steroid with a mineral acid to obtain estr-4-ene-3,l7-dione.

6. A process for the reduction of an aromatic steroid into the corersponding 2,5(10)-diene steroid which comprises electrochemically reducing said aromatic steroid at a cathode selected from the group consisting of aluminum, carbon, copper, lead, graphite and platinum in an electrolytic medium comprising a solvent selected from the group consisting of a lower aliphatic amine, liquid ammonia, and mixtures thereof and an electrolyte selected from the group consisting of lithium chloride, lithium bromide and lithium iodide.

7. A process according to claim 6 wherein said aromatic steroid is selected from the group consisting of 3-alkyl ethers, 3-cycloalkyl ethers, and S-aralkyl ethers of 1,3,5 (10)-trienes of the estrane, 19-nor-pregnane, and l9-norcholestane series.

8. A process according to claim 7 wherein said cathode is aluminum and said solvent is a lower aliphatic amine.

9. A process according to claim 7 wherein said cathode is aluminum, said solvent is ethylenediamine, and said electrolyte is lithium chloride.

10. A process according to claim 9 wherein said aromatic steroid is 3-methoxy-17-cycloethylenedioxyestra-1,3, 5 (10)-triene.

References Cited UNITED STATES PATENTS 3,332,968 7/19'67 Joly et al n 260-397.3

HOWARD S. WILLIAMS, Primary Examiner.

H. M. FLOURNOY, Assistant Examiner.

US. Cl. X.R. 

1. A PROCESS FOR THE PRODUCTION OF 19-NOR-3-OXO STEROIDS WHICH COMPRISES REDUCING AN AROMATIC STEROID BY ELECTROCHEMICAL REDUCTION AT A CATHODE SELECTED FROM THE GROUP CONSISTING OF ALUMINUM, CARBON, COPPER, LEAD, GRAPHITE AND PLATINUM IN AN ELECTROLYTIC MEDIUM COMPRISING A SOLVENT SELECTED FROM THE GROUP CONSISTING OF A LOWER ALIPHATIC AMINE, LIQUID AMMONIA, AND MIXTURES THEREOF AND AN ELECTROLYTE SELECTED FROM THE GROUP CONSISTING OF LITHIUM CHLORIDE, LITHIUM BROMIDE AND LITHIUM IODIDE TO OBTAIN THE CORRESPONDING 2,5(10)-DIENE STEROID, AND SUBJECTING SAID 2,5(10)-DIENE TO ACID HYDROLYSIS TO OBTAIN SAID 19-NOR-3OXO STEROID. 